Early Switch and Early Discharge Opportunities in Intravenous Vancomycin Treatment of Suspected Methicillin-Resistant Staphylococcal Species Infections

BACKGROUND: Patients with methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase negative staphylococci (MR-CoNS) infections are usually treated with intravenous (IV) vancomycin and remain hospitalized for the duration of IV therapy. Oral linezolid has excellent bioavailability and activity against MRSA and MR-CoNS and offers the potential for outpatient treatment of MRSA and MR-CoNS infections. OBJECTIVES: To determine the potential for early switch (ES) from IV vancomycin to oral linezolid and subsequent early discharge (ED) in hospitalized, adult patients treated for an MRSA or MR-CoNS infection. METHODS: We conducted a retrospective cohort study at the Veterans Administration Greater Los Angeles Healthcare System from January 1 through December 31, 2000. Potential reductions in vancomycin use, hospital length of stay (LOS), and economic savings were determined. RESULTS: A total of 103 of 177 (58%) treatment courses for MRSA or MR-CoNS infections were potentially eligible for ES, with annual and mean decreases in vancomycin use of 535 defined daily doses and 5.2 days per event. Of the ES cohort, 55 of 103 (53%) courses were potentially eligible for ED, with an annual and mean reduction in LOS of 181 days and 3.3 days per event. The total potential savings was $220,181, at an average of $3,478 per event. CONCLUSIONS: Early switch to oral linezolid for treatment of MRSA or MR-CoNS infections could reduce vancomycin use, hospital length of stay, and economic costs.

M ethicillin-resistant Staphylococcus aureus (MRSA) is a virulent pathogen traditionally associated with severe nosocomial infections. Methicillin-resistant coagulase negative staphylococci (MR-CoNS) is occasionally associated with infection, usually catheter-related. With a few notable exceptions, epidemiologic studies in the United States and Western Europe have demonstrated increasing prevalence rates for MRSA and MR-CoNS over the past 2 decades. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] Data from the 1997 to 1999 SENTRY Antimicrobial Surveillance Program show that MRSA accounts for 34% of all U.S. nosocomial S. aureus isolates. 16 Furthermore, data from the 2000 Healthcare Cost and Utilization Project Nationwide Inpatient Sample 17 sponsored by the Agency for Healthcare Research and Quality show that S. aureus is implicated in 634 per 100,000 hospital discharges. These figures suggest that MRSA is implicated in 217 per 100,000 hospital discharges in the United States. Community-acquired MRSA infections are also becoming more common and represent a new threat to patients outside of the hospital setting. [8][9][10][11] A comparison of outcomes between MRSA and methicillinsensitive S. aureus (MSSA) infections suggests a higher patient mortality rate with the resistant strains (21% versus 8%). 7 Also, results from a cohort study show that MR-CoNS bacteremia is associated with a higher mortality rate and longer length of stay as compared to matched controls. 18 At present, therapeutic options for reliably (with 99% to 100% activity) treating MRSA and MR-CoNS include vancomycin, teicoplanin, quinopristin-dalfopristin, and linezolid (Zyvox-Pfizer). Vancomycin has become the drug of choice for treating MRSA infections due primarily to its low cost and relatively low toxicity. However, reliance solely on vancomycin for control of MRSA is suboptimal because this antibiotic requires both therapeutic drug monitoring and intravenous (IV) administration, exerts selective pressure on a hospital' s microbial flora, and does not have comparable bactericidal activity when compared to ß-lactam antimicrobials in the treatment of serious MSSA infections. 14,19,20 Staphylococcal intermediate resistance [21][22][23] and full resistance 24 to vancomycin have also been reported.
The inpatient costs of treating MRSA infections with IV antibiotics are significant, and there is an increasing need to provide effective treatment of MRSA in the outpatient setting. The annual national pecuniary burden due to MRSA in a Canadian model approximates $42 million to $59 million. 25 The excess expenditures for MRSA infections are a result of longer hospitalizations, isolation of infected or colonized patients, infection control screening programs, and administration of IV. 7,25,26 Oral linezolid (Zyvox) has excellent bioavailability and activity against MRSA and MR-CoNS. Linezolid is the first oxazolidinone antimicrobial approved for the treatment of MRSA and MR-CoNS infections. The efficacy of linezolid for MRSA and MR-CoNS infections when compared to standard therapy is favorable. Microbiologic and clinical cure rates with linezolid are equivalent to ß-lactam therapy of MSSA skin and soft tissue infections and vancomycin treatment of MRSA-related nosocomial pneumonia. 27,28 The 100% oral bioavailability of linezolid may allow for early switch (ES) to oral therapy for MRSA and MR-CoNS infections. 29,30 Several studies have affirmed the safety and efficacy of switching patients who are clinically stable to appropriate oral antibiotics in order to decrease hospital length of stay (LOS) for a variety of infections. [31][32][33][34][35][36][37][38] Data from a phase III clinical trial comparing the clinical efficacies of linezolid and vancomycin support the potential for linezolid ES for MRSA infections. This study shows that similar outcomes are observed with each agent, and a potential decrease in LOS is demonstrated for complicated skin and soft-tissue infection during the initial 2 weeks of hospitalization. 39 We have conducted a retrospective cohort study to evaluate the potential (not actual, as no intervention has been performed) opportunity for decreased vancomycin use, shorter LOS, and resulting economic benefits of linezolid oral switch therapy for patients with MRSA and MR-CoNS infections. Patient characteristics predictive of eligibility for ES and early discharge (ED) from the hospital are assessed.

Early Switch and Early Discharge Opportunities in Intravenous Vancomycin Treatment of Suspected Methicillin-Resistant Staphylococcal Species Infections
Criteria for Early Switch (ES) and Early Discharge (ED)

■■ Materials and Methods Patient Identification
The Veterans Administration Greater Los Angeles Healthcare System (GLA) inpatient facility is a 583-bed tertiary-care teaching hospital. All patients older than or equal to 18 years who were hospitalized during a full vancomycin treatment course of a microbiologically confirmed or presumed infection with MRSA or MR-CoNS were identified through a review of pharmacy and microbiology records from January 1 through December 31, 2000. A full treatment course was defined as the therapeutic administration of vancomycin for at least 7 consecutive days. A single dose of vancomycin was considered therapeutic for 7 days in patients dependent on hemodialysis. A defined daily dose was the amount of vancomycin required to achieve daily therapeutic trough levels (>10 µg/mL) for a given patient. Microbiologic confirmation of MRSA or MR-CoNS infection required either 1 culture positive from a sterile body site or a nonsterile site supported by clinical evidence of infection. Presumed infection was defined as a clinical assessment of suspected MRSA or MR-CoNS infection without microbiologic confirmation. We included patients with presumed infection in our analysis because, in some instances (e.g., patients with MRSA colonization or prior MRSA infection or patients with clinical evidence of line sepsis, presumably due to MR-CoNS), the posttest probability for infection with MRSA or MR-CoNS remained high despite negative culture results. All isolates were identified with standard microbiologic methods, and susceptibility testing was performed according to the guidelines of the National Committee for Clinical Laboratory Standards.
The following conditions excluded patients from further analysis: transfer to another acute-care facility, death during hospitalization while on vancomycin therapy, or a diagnosis of microbiologically documented or presumed MRSA or MR-CoNS endocarditis or osteomyelitis. We excluded patients with MRSA or MR-CoNS endocarditis or osteomyelitis from our study because these patients would have required an extended course of antibiotics (often 4 to 6 weeks), and the safety profile of long-term use of linezolid has not been well established. In the absence of these safety data, we determined that we could not accurately determine the true cost savings of ES and ED with oral linezolid for these patients. Hospital acquisition of an infection was defined as isolation and initiation of treatment for MRSA or MR-CoNS greater than 48 hours after admission.
Demographic data, including age, gender, nursing home resident status, admit and discharge ward, requirement for intensive care unit (ICU) treatment, and comorbid conditions, were collected for all patients meeting the above criteria. A patient could have more than one vancomycin course included in the study if the additional treatments were indicated for an infection at a different site, a new infection at the original site occurring at least 7 days after clinical cure of the preceding infection, or continuous vancomycin administration through more than one hospitalization. Patients with positive MRSA or MR-CoNS cultures were evaluated for type of isolate (e.g. MRSA, MR-CoNS), site, and number of positive specimens. Cultures were clinically relevant if they correlated with the documented site of infection and were obtained in the 3 days prior to or 2 days after the initiation of vancomycin. Isolation of MR-CoNS was clinically relevant only with documentation of active infection regardless of the site and sterility of the specimen. MRSA or MR-CoNS isolation in the 30 days prior to hospitalization was considered chronic colonization. Infection or colonization with vancomycin resistant enterococci (VRE) was also recorded. Duration and timing of vancomycin administration with respect to hospital admission, discharge, and clinically relevant MRSA or MR-CoNS positive cultures were obtained for each treatment course. Discharge disposition and duration of hospitalization were outcome measures. The GLA Institutional Review Board approved the study design and methods of data collection.

Early Switch and Early Discharge Criteria
Qualification for ES or ED required fulfillment of all respective criteria listed in Table 1 at least 1 day prior to recorded hospital discharge. All treatment courses were evaluated for ES; however, ED was assessed for only the ES-eligible cohort. Certain MRSA and MR-CoNS infections were ineligible for ES (but still eligible for inclusion in the study), including meningitis, septic arthritis, and septic thrombophlebitis. The reason for this was because, at present, linezolid is not approved for use in these areas, and we did not wish to promote directly or indirectly the unapproved usage of linezolid. Patients who were eligible for ES but who were not eligi- ble for ED on the same day as ES received a reevaluation of each subsequent hospital day to ensure that they remained eligible for ES while hospitalized. Patients who had a single relapse in their clinical condition (e.g., developed 1 episode of fever) but who otherwise fulfilled all other ES criteria remained eligible for continuation on oral therapy. Two authors (Parodi and Rhew) reviewed the data for criteria for ES and ED and a third author (Goetz) served to resolve differences of opinion. Univariate and multivariate analyses were performed to determine the independent predictors of eligibility for ES and ED.

Cost Analysis
We performed a cost analysis using drug acquisition costs and specialty-based hospital costs (Table 2). Hospital costs were obtained from the GLA's computerized cost-accounting system called the Decision Support System. 40 The individual costs for each patient' s hospitalization were not readily available. Thus, the mean cost (not charge) per day of the hospital bed type (e.g., medical, surgical, ICU, etc.) occupied at the time of ED was obtained. The total bed cost consisted of the nursing, laboratory, pharmaceutical, radiological, surgical, and miscellaneous costs. The cost of isolation of MRSA patients was not calculated because patients on the regular medicine wards, who are either infected or colonized with MRSA, are not isolated or cohorted at GLA.
The potential economic impact of oral linezolid therapy on MRSA or MR-CoNS infections was calculated for patients eligible for ED only. The cost savings for ES without ED were not calculated because the difference in drug costs between generic vancomycin and linezolid was relatively insignificant as compared to the added expense of continued hospitalization.

Statistical Analysis
Statistical analysis was performed using EpiInfo version 6.04c and SPSS version 11.0 (Centers for Disease Control, Atlanta, GA. http://www.cdc.gov/epiinfo/epimanual.htm). The cohorts eligible and not eligible for linezolid ES were compared to identify the predictive variables of ES. ED predictors were calculated from the subset of vancomycin courses eligible for ES. All categorical variables were compared using the uncorrected χ 2 or the Fisher exact test, as appropriate. Continuous variables were evaluated with Student' s t or Mann-Whitney tests for normal and nonnormally distributed data, respectively. A conditional stepwise logistic regression model included all significant univariate ES and ED predictors. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. A P value of less than 0.05 was considered significant.  Table 3. Most patients (92.8%) had at least 1 comorbid condition, and 33 (23.9%) had 3 or more active medical problems. A wide range of MRSA or MR-CoNS infections were treated.
Eighty-six (48.6%) of the treatment courses were for infections not hospital-acquired. Most of these patients had 1 or more underlying risk factors for MRSA or MR-CoNS infection, including the following: resident of a chronic care facility (34.8%), chronic indwelling catheters (e.g., intravenous or urinary, 32.6%), known previous hospitalization during the

Microbiologic Characteristics
The general microbiologic characteristics for the patient population are outlined in Table 4. Most (70.9%) of the clinically rel-evant cultures were positive for MRSA. One third of all infections were complicated by bacteremia, and 29 (49.1%) of these bacteremias were due to MRSA. Chronic MRSA or MR-CoNS colonization was documented in 35 (27.5%) of the cases. VRE colonization or infection occurred in 21 (11.9%) of the treatment events, with urine (52.4%) and blood (23.8%) comprising the most common sites of isolation.

Treatment
The mean duration of therapy with vancomycin was 16.6 ± 13.5 days. When a clinically relevant MRSA or MR-CoNS culture was present, vancomycin was started within 1.61 ± 1.70 days. Vancomycin was initiated an average of 9.72 ± 15.4 days after the admission date. Adjunct procedures aimed at removing the focus of MRSA or MR-CoNS infection were required in 65 (36.7%) of the treatment events, and 7 (4.0%) episodes necessitated a second intervention. Central venous catheter removal (43.0%), surgical procedures (26.2%), foley/suprapubic catheter changes (15.6%), and bedside abscess incision and drainage (13.8%) were the most common adjunct therapies.

Potential for Early Switch and Early Discharge With Oral Linezolid
The first and second investigators reached agreement with respect to ES and ED eligibility and timing in greater than 90% of the episodes. There were 12 (6.8%) and 8 (7.8%) conflicts regarding ES and ED qualification, respectively. The third investigator was able to resolve all differences of opinion utilizing the judgment made by either the first or second investigator.
A total of 103 (58.2%) episodes were potentially eligible for ES to oral linezolid and 55 (31.1%) for ED. The reasons for not qualifying for ES or ED are listed in Table 5. Presumed or confirmed infection with resistant gram-negative organisms in cases of nosocomial pneumonia (8 episodes), line infection (3), intra-abdominal abscess (1), urinary tract infection (1), and cellulitis (1) preempted ES to oral linezolid in 14 (7.9%) of the episodes. If a patient qualified for ES, the most common reason preventing ED was an unstable comorbid condition.
The significant patient characteristics predictive of eligibility for ES and ED are listed in Table 6. Independent predictors of ES were no complex primary diagnosis requiring continued intravenous vancomycin, lack of VRE colonization or infection, no diagnosis of pneumonia, the absence of a pulmonary comorbidity, having a culture positive for MRSA regardless of clinical significance, and shorter duration of vancomycin therapy. ED predictors included shorter hospitalization, younger age, and no requirement for ICU care. Comparisons between patients eligible and not eligible for ES and similar comparisons for patients eligible and not eligible for ED are presented in Table 7.
A sensitivity analysis for ES and ED predictors was subsequently performed that excluded treatment courses for complex MRSA or MR-CoNS infections (e.g., meningitis, infections  P<0.001). There were no significant differences with respect to age, gender, primary diagnoses, and discharge disposition.

Outcomes and Economic Analysis
More than half of the patients (98 of 177, 55.4%) required discharge to a long-term care facility or nursing home after their treatment course. The remaining cases were discharged to home (51 of 177, 28.8%) and acute rehabilitation (28 of 177, 15.8%). Table 8 illustrates the prospective potential savings affected by ES to oral linezolid followed by ED. The mean savings per eligible treatment course in vancomycin use and LOS were 5.2 and 3.3 days, respectively. The overall potential savings amounted to $220,181. The mean savings per treatment course was $4,003 ± $3,631. However, the 2 episodes with the largest decreases in hospitalization had estimated cost savings of greater than $15,000, which was more than 50% greater than the next set of data points. Thus, these outlying values were subsequently excluded from the calculation of the mean, leaving a final savings of $3,478 ± $2,392 per episode.

Relevance of Findings
We found that, in our facility, many patients with a broad range of MRSA or MR-CoNS infections often remain hospitalized to receive intravenous vancomycin after achievement of clinical stability. A significant number of these patients could avoid prolonged hospital confinement and subsequent morbidity by applying linezolid ES and ED. The potential economic savings due to this intervention are substantial (although the large standard deviations around our cost-savings calculations may   potentially limit the economic benefits of applying ED). Other possible benefits from ES and ED include improved patient satisfaction with their care, 41 removal of intravenous lines, and a reduction in the risk of acquiring new nosocomial infections. 42 The advantages to ES and ED are not limited to the individual patient. Early discharge effectively diminishes the reservoir of MRSA or MR-CoNS-infected patients from the hospital population. This outcome is desirable for several reasons. First, the number of opportunities for transmission of MRSA or MR-CoNS to noncolonized patients or health care workers is reduced. 43 Second, the concomitant decline in vancomycin use would decrease selective pressure for resistant organisms such as VRE. 23 Finally, fewer hospitalized MRSA or MR-CoNS patients would free otherwise-committed human and financial resources for intensified infection control measures such as surveillance, contact isolation, personnel education, and improved antimicrobial utilization programs. 14 Greater savings might be possible with disease processes requiring prolonged therapy such as MRSA or MR-CoNS endocarditis or osteomyelitis. Clinical experience using linezolid for either of these conditions is limited, and, to date, the agent does not have an approved indication for their treatment. 44,45 For these reasons, we excluded such infections from our analysis. Even if such therapy was validated, long-term linezolid is not without risk because of the potential for emergence of resistance and development of drug toxicity. MRSA resistance to linezolid is difficult to induce in vivo but has occurred in a patient with an infected peritoneal dialysis catheter that was not removed during a month of continuous linezolid therapy. 29,30,46,47 Discharge of such patients to long-term care facilities, where MRSA control measures may be limited, raises the possibility of transmission of linezolid resistant S. aureus strains in the community. Furthermore, approximately one third of patients experience reversible thrombocytopenia after 10 days of linezolid therapy. 48 Anemia and pancytopenia are other adverse outcomes associated with prolonged treatment. 49,50 The implementation of successful ES therapy for MRSA or MR-CoNS infections will require appropriate patient selection with respect to the type of infection, absence of prosthetic material or undrained foci of infection, and the ability to tolerate therapy.

■■ Limitations
Our study had several limitations. First, in our economic analysis, individual costs for each patient were unavailable, which required us to perform estimations rather than use patient-specific data.
Second, we did not include the impact of ES with oral linezolid on subsequent hospitalizations, although we have no reason to believe that subsequent hospital admissions would either decrease or increase with the application of ES with linezolid. We also did not address the potential for adverse effects secondary to linezolid and the costs associated with treating those adverse events. However, in our study, we excluded patients from ES who had contraindications to linezolid. The potential for patient noncompliance with outpatient oral linezolid treatment was not incorporated into our economic modeling assumptions, although the once-daily dosing of linezolid is likely to enhance compliance with this medication. A formal cost-effectiveness analysis could have incorporated all of these factors as well as facilitated sensitivity analyses around our assumptions, but this was beyond the scope of our study objectives. Third, the ES eligibility criteria should serve as a starting point to identify patients for switch therapy and may not necessarily incorporate all relevant factors. The independent predictors of age, ICU requirement, MRSA or MR-CoNS culture positive status, VRE colonization or infection, and the type of MRSA or MR-CoNS infection could also aid in patient selection. Some of these factors are known at the time of admission, and all can be established before the time of discharge. Ultimately, sound clinical judgment, which synthesizes the application of the above criteria as well as each patient' s unique characteristics, will be required for successful oral linezolid therapy of these infections.

Predictors of Eligibility for Early Switch (ES) and Early Discharge (ED)
Fourth, our study was performed in a VA hospital system, and this limits our ability to extrapolate our findings to the experience of a typical community hospital or health system. For example, a potential alternative to oral linezolid is the out-patient administration of vancomycin. Since our institution does not provide outpatient intravenous antimicrobials, our cost analysis may overestimate the actual savings possible at other institutions that have such programs in place. Nonetheless, the baseline-allowed cost of outpatient vancomycin treatment still varies between $90 and $200 per day, depending on the type of insurance payer. 51 Device-related complications, infections, serum trough-level checks, and infusion-related adverse events all make outpatient vancomycin a more costly alternative than oral linezolid. 52 Regardless of whether any of the above potential complications ever occur, the acquisition cost of oral linezolid at our facility is still less than the basic costs of vancomycin treatment. One might also speculate that patient satisfaction would be improved with oral treatment.
Finally, a randomized controlled trial (RCT) has demonstrated that patients with complicated skin and soft tissue infections who are treated with linezolid (IV followed by oral) experience a shorter LOS as compared to patients treated with IV vancomycin (9 versus 14 days, P=0.052). 53 While not an RCT, our study evaluated the potential economic benefit of IV to oral switch with linezolid in a broader range of patients with MRSA and MR-CoNS infection. In fact, the greatest opportunity for cost savings occurred in patients with MRSA pneumonia, followed by MRSA skin and soft tissue infections. Our study also evaluated the potential for ES and ED for all eligible patients in a "real-world" setting and did not limit its evaluation to patients enrolled in a clinical trial.

■■ Conclusion
Our study shows that oral switch therapy with linezolid appears to offer the potential for decreased vancomycin utilization, decreased LOS, and significant cost savings. Furthermore, we have shown that criteria for ES and ED can be developed and easily applied to identify ES and ED candidates. Validation of these results will require a prospective clinical trial of early switch to linezolid therapy that carefully assesses a variety of clinical outcomes, including relapse rates, emergence of resistance, and adverse events. Given the increased prevalence of MRSA and the limited treatment options available for this organism, new approaches are needed to diminish the impact of these infections on society and our health care system.

ACKNOWLEDGMENTS
The authors thank Jeffrey Sayers, PharmD, and Mickey Amos for their assistance in obtaining the GLA vancomycin pharmacy and MRSA and MR-CoNS laboratory data. The authors also thank William Schwartzman, MD, for his assistance in the identification of cases.  Outcomes and Economic Analyses